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Blood, 1 January 2006, Vol. 107, No. 1, pp. 328-333.
Prepublished online as a Blood First Edition Paper on September 1, 2005; DOI 10.1182/blood-2005-05-2049.
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RED CELLS
The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study
Elizabeta Nemeth,
Gloria C. Preza,
Chun-Ling Jung,
Jerry Kaplan,
Alan J. Waring, and
Tomas Ganz
From the Department of Medicine, David Geffen School of Medicine, Los Angeles, CA; the Department of Pathology, David Geffen School of Medicine, Los Angeles, CA; and the Department of Pathology, School of Medicine, University of Utah, Salt Lake City, UT.
Hepcidin is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid (aa) peptide has a hairpin structure stabilized by 4 disulfide bonds. We synthesized a series of hepcidin derivatives and determined their bioactivity in a cell line expressing ferroportin-GFP fusion protein, by measuring the degradation of ferroportin-GFP and the accumulation of ferritin after peptide treatment. Bioactivity was also assayed in mice by the induction of hypoferremia. Serial deletion of N-terminal amino acids caused progressive decrease in activity which was completely lost when 5 N-terminal aa's were deleted. Synthetic 3-aa and 6-aa N-terminal peptides alone, however, did not internalize ferroportin and did not interfere with ferroportin internalization by native hepcidin. Deletion of 2 C-terminal aa's did not affect peptide activity. Removal of individual disulfide bonds by pairwise substitution of cysteines with alanines also did not affect peptide activity in vitro. However, these peptides were less active in vivo, likely because of their decreased stability in circulation. G71D and K83R, substitutions previously described in humans, did not affect hepcidin activity. Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations.
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